On the Spectrum

Chapter 8
stable relationships, and affect their ability to function in school or in a professional career
(Constantino 2011).
Endophenotypes in the broader sense can be behavioral, cognitive, neurobiological
or genetic (Sucksmith et al. 2011). It is important to comment here that there are many
potential substrates that could serve as dimensional measures of ASD in the context of
neuroimaging research and that different endophenotypes could lead to identification of
different neurobiological markers. However, in this thesis, we consistently focused on the
social dimension of autistic traits, which is thought to be the central feature of impairment.
In this thesis, against the background of the continuous nature of ASD, we assessed
whether the brain correlates of ASD are present on a continuum as well. Symptoms of ASD
are thought to be associated with altered development of the brain, in terms of structural
development and growth, but also in functional development. Appreciating that traits of ASD
form a severity continuum, it is actually quite intuitive to assume that the underlying brain
characteristics are not just present in the most severely affected individuals but may form a
continuum in the population as well. We addressed this question tapping into several stages
of brain development, investigating various different characteristics of the brain.
The neurobiology of autistic traits throughout the lifespan
Symptoms of ASD become apparent early in life, and although symptoms are not always
recognized immediately, retrospective developmental histories of patients usually point
to symptoms appearing in the first year of life (Ozonoff, Heung, Byrd, Hansen and Hertz-
Picciotto 2008). There is some evidence that environmental exposures during pregnancy,
such as prenatal infections and medication use of the mother contribute to the risk of
ASD (Brown 2012; El Marroun, White, van der Knaap, Homberg, Fernandez et al. 2014). A
seminal postmortem study in children diagnosed with ASD suggested abnormal development
of cortical architecture (Stoner, Chow, Boyle, Sunkin, Mouton et al. 2014). Interestingly,
histopathological studies point to increased expression of ASD candidate genes in the fetal
cortex, although the role of these genes in prenatal brain growth has not been established
yet (Willsey, Sanders, Li, Dong, Tebbenkamp et al. 2013; Birnbaum, Jaffe, Hyde, Kleinman
and Weinberger 2014). Taken together, this points to a crucial role of the prenatal period, as
the brain differentiates from the ectoderm early in gestation to form a vastly complex organ
by birth (Andersen 2003). In utero, the size of the skull, that can be assessed during routine
ultrasound measurements, provides a good measure of brain size (Cooke, Lucas, Yudkin
and Pryse-Davies 1977). In chapter 3, we evaluated prenatal trajectories of head growth in
relation to later autistic symptoms. We found that children with slower prenatal head growth
showed more traits of ASD later in life. This is supportive of the notion that prenatal brain
growth differences may be involved in the neurobiology of ASD. However, we did not see
this same pattern in children with clinically diagnosed ASD. Speculatively, the heterogeneity
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